Methods for identifying compounds useful in treating type II diabetes
Methods for identifying compounds, which modulate the bioactivity of human hepatic nuclear factor-1 (HNF-1), and which are therefore useful in treating type II diabetes are disclosed.
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Claims
1. A method for aiding in the identification of a compound for use in treating Type II diabetes comprising the steps of:
- a) incubating a cell in the presence and absence of a test compound, wherein said cells been altered to contain a nucleic acid molecule comprising an HNF1 response element operably linked to a reporter gene and said cell expresses a wild-type HNF1 protein;
- b) determining the level of expression of said reporter gene in said cell incubated in the presence and absence of said test compound; and
- c) selecting a compound that induces a higher level of expression of said reporter gene in step (b) than that expressed in the absence of said compound, for use in treating Type II diabetes.
2. The method of claim 1, wherein said HNF1 response element is contained in a promoter selected from the group consisting of: liver specific glucokinase, glucose transporter, pyruvate kinase, albumin, aldolase B, UDP-N-acetylglucosamine, an alcohol dehydrogenase, cytochrome P-450, aminopeptidase N, phenylalaninehydroxylase, tyrosine aminotransferase, hepatic triglyceride lipase, apolipoprotein B, apolipoprotein A-II, cholesterol 7 alpha-hydrolase, fibrinogen, alpha-1-microglobulin, C4b-binding protein insulin like growth factor 1 (IGF-1), alpha-fetoprotein, and neural cell adhesion molecule (N-CAM).
3. The method of claim 1, wherein said HNF1 response element is contained in an albumin promoter.
4. The method of claim 1, wherein said cell further expresses a mutant HNF1 protein selected from the group consisting of: an HNF1 protein encoded by a nucleic acid molecule having a base substitution at nucleotide 414 which results in a substitution of an arginine by a tryptophan in the wild-type HNF1 amino acid sequence and an HNF1 protein encoded by a nucleic acid molecule having a nucleotide insertion at nucleotide 895 resulting in a frameshift mutation at residue 895.
5. The method of claim 2, wherein said cell further expresses a mutant HNF1 protein selected from the group consisting of: an HNF1 protein encoded by a nucleic acid molecule having a base substitution at nucleotide 414 which results in a substitution of an arginine by a tryptophan in the wild-type HNF1 amino acid sequence and an HNF1 protein encoded by a nucleic acid molecule having a nucleotide insertion at nucleotide 895 resulting in a frameshift mutation at residue 895.
6. The method of claim 2, wherein said reporter gene is a luciferase gene.
7. The method of claim 3, wherein said reporter gene is a luciferase gene.
8. The method of claim 4, wherein said reporter gene is a luciferase gene.
9. The method of claim 5, wherein said reporter gene is a luciferase gene.
10. A method for identifying a compound for use in treating Type II diabetes comprising the steps of:
- a) incubating a pancreatic cell in the presence and absence of a test compound, wherein said cell has been altered to contain a nucleic acid molecule which encodes HNF1 and said cell produces insulin;
- b) determining the level of insulin expression in said cell incubated in the presence and absence of said test compound; and
- c) selecting a compound that induces a higher level of insulin expression than that expressed in the absence of said compound for use in treating Type II diabetes.
| WO 92/11365 | July 1992 | WOX |
| WO 94/00558 | January 1994 | WOX |
- Byrne, Maria M. et al., "Altered Insulin Secretory Responses to Glucose in Diabetic and Nondiabetic Subjects with Mutations in the Diabetes Susceptibility Gene MODY3 on Chromosome 12", Diabetes 45:1503-1510, Nov. 1996. Fajans, Stefan S. et al., "Maturity-Onset Diabetes of the Young", Life Sciences, 6(55):413-422, 1994. Vaxillaire, Martine et al., "A Gene for Maturity Onset Diabetes of the Young (MODY) Maps to Chromosome 12q", Natural Genetics 9:418-423, Apr. 1995. Zhong, Weimin et al., "Tissue-Specific Regulation of Mouse Hepatocyte Nuclear Factor 4 Expression", Molecular and Cellular Biology 11(14):7276-7284, Nov. 1994. Barrera-Hernandez, Gonzalo et al., "Effects of Diabetes Mellitus on Hepatocyte Nuclear Factor 1 Decrease Albumin Gene Transcription", The Journal of Biological Chemistry, 17(271):9969-9975, Apr. 1996. Bach, Ingolf and Yaniv, Moshe "More Potent Transcriptional Activators or a Transdominant Inhibitor of the HNF1 Homeoprotein Family are Generated by Alternative RNA Processing", The EMBO Journal, 11(12)4229-4242 (and corrigendum), 1993. Ringeisen, Fran.cedilla.ois, et al., "The Transactivation Potential of Variant Hepatocyte Nuclear Factor 1 is Modified by Alternative Splicing", The Journal of Biological Chemistry 34(268):25706-25711, 1992. Stoffel, Markus et al. "A Yeast Artificial Chromosome-Based Map of the Region of Chromosome 20 Containing the Diabetes-Susceptibility Gene, MODY1, and a Myeloid Leukemia Related Gene", Proc. Natl. Acad. Sci., USA 93:3937-3941, 1996. Bryne, Maria M. et al., "Altered Insulin Secretory Responses to Glucose in Subjects with a Mutation in the MODY1 Gene on Chromosome 20", Diabetes 44:699-704, 1995. Vaxillaire, Martine et al., "Search for a Third Susceptibility Gene for Maturity-Onset Diabetes of the Young", Diabetes 43:389-395, 1994. Drewes, Thorsten et al. "Human Hepatocyte Nuclear Factor 4 Isoforms are Encoded by Distinct and Differentially Expressed Genes" Molecular and Cellular Biology 3(16):925-931, 1996. Beck-Nielsen, Henning et al., "Insulin Action and Insulin Secretion in Identical Twins with MODY", Diabetes 37:730-735, 1988. Lesage, Suzanne, et al. "Linkage Analyses of the MODY3 Locus on Chromosome 12q with Late-Onset NIDDM", Diabetes 44:1243-1247, 1995.
Type: Grant
Filed: Jan 10, 1997
Date of Patent: Aug 18, 1998
Assignee: Millennium Pharmaceuticals, Inc. (Cambridge, MA)
Inventor: M. Alexandra Glucksmann (Somerville, MA)
Primary Examiner: David Saunders
Assistant Examiner: F. Pierre VanderVegt
Attorney: Beth E. Foley, Hoag & Eliot LLP Arnold, Esq.
Application Number: 8/782,047
International Classification: C12Q 102; C12Q 166; C12Q 168; C07H 2104;
